Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-21
2002-04-23
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06376501
ABSTRACT:
This application is a 371 of PCT/JP98/05779, filed Dec. 21, 1998.
TECHNICAL FIELD
The present invention generally relates to pharmaceutical compositions comprising as an active ingredient a compound having purine structure, and specifically relates to a type 2 helper T cell (hereinafter abbreviated to “Th2”)-selective immune response inhibitor and an immune response regulator. More specifically, the present invention relates to a Th2-selective immune response inhibitor and an immune response regulator which can effectively treat or prevent those diseases attributable to abnormal rise immunize response on the Th2 side (i.e. allergic diseases such as asthma, allergic dermatitis or allergic rhinitis, or autoimmune diseases such as systemic lupus erythematosus) by inhibiting immune response on the Th2 side and enhancing immune response on the type 1 helper T cell (hereinafter abbreviated to “Th1”) side.
BACKGROUND ART
What is playing the major role in immune response is helper T cells. There are two classes, Th1 and Th2, in helper T cells. Cytokines produced when Th1 is activated include interleukin-2 (IL-2) and interferon-&ggr; (IFN-&ggr;); and cytokines produced when Th2 is activated include interleukin-4 (IL-4) and interleukin-5 (IL-5). Cytokines on the Th1 side induce activation of macrophages and natural killer cells, and are mainly involved in cellular immunity such as infection control against viruses and bacteria. On the other hand, it is known that cytokines on the Th2 side are involved in humoral immunity such as antibody production from B cells. Particularly, IL-4 not only induces production of IgE antibody by B cells, but also has an action of differentiating and proliferating Th2 cells. IL-5 has various actions such as activation, differentiation/proliferation and lifetime prolongation of eosinophils, and plays an important role in allergic inflammation. Thus, it is considered that allergic inflammation is caused by abnormal rise in immune response on the Th2 side. Actually, the presence of IL-4 and IL-5 has been confirmed in affected parts of asthma patients and patients with atopic dermatitis.
Conventionally, asthma, atopic dermatitis and the like have been treated with anti-allergic agents. However, such agents do not inhibit the immune response by Th2; as in the case of histamine, they only inhibit a part of allergic reactions in the downstream. Thus, their clinical effect is insufficient. Consequently, only steroids have been proved effective against these diseases. However, long term administration of steroids causes wide-ranging side effects (diabetes, infections, adrenal dysfunction, moon face, etc.). Since steroids inhibit immune response on both the Th1 side and the Th2 side, administration of steroids results in the lowering of patients' resistance to viral infections as their immune response is lowered. In order to overcome this drawback, a drug which inhibits immune response on the Th2 side and simultaneously enhances immune response on the Th1 side can be said more preferable since such a drug has an advantage of preventing infections caused by virus or the like.
From what has been described so far, it is considered that if a drug which enhances immune response on the Th1 side represented by production of IFN-&ggr; and inhibits immune response on the Th2 side represented by production of IL-4 and IL-5 is developed, the drug will be an effective and highly safe therapeutic or prophylactic for allergic diseases
Autoimmune diseases such as systemic lupus erythematosus are also presumed to be a state in which immune response on the Th2 side has been abnormally exasperated (Medical Immunology, 15, 401, 1985). Thus, a drug which enhances immune response on the Th1 side and inhibits immune response on the Th2 side as described above is expected to be a therapeutic for autoimmune diseases.
DISCLOSURE OF THE INVENTION
Under such circumstances, it is an object of the present invention to provide an effective therapeutic for allergic diseases caused by abnormal rise in immune response on the Th2 side, which therapeutic treats allergic diseases by enhancing immune response on the Th1 side represented by production of IFN-&ggr;, etc. and simultaneously inhibiting immune response on the Th2 side represented by production of IL-4, IL-5, etc.
As a result of extensive and intensive researches to develop a drug which enhances immune response on the Th1 side represented by production of IFN-&ggr;, etc. and simultaneously inhibits immune response on the Th2 side represented by production of IL-4, IL-5, etc., the prevent inventors have found that purine derivatives having a specific structure enhance immune response on the Th1 side and inhibit immune response on the Th2 side. Thus, the present invention has been achieved.
The present invention relates to a type 2 helper T cell-selective immune response inhibitor and an immune response regulator, individually comprising, as an active ingredient, a purine derivative represented by General Formula (I):
wherein
R
2
is hydrogen or a C
1-14
hydrocarbon group in which —CH
2
— not directly bound to the purine skeleton and CH
2
in —CH
3
not directly bound to the purine skeleton may be substituted by carbonyl, sulfonyl, —O— or —S—; ═CH
2
may be substituted by ═O or ═S; C—H in —CH
2
— not directly bound to the purine skeleton, C—H in —CH
3
not directly bound to the purine skeleton, C—H in >CH— not directly bound to the purine skeleton, C—H in ═CH— not directly bound to the purine skeleton and C—H in ═CH
2
may be substituted by N, C-halogen or C—CN;
R
6
is hydroxyl, amino or amino which is mono- or di-substituted by a C
1-10
hydrocarbon group(s);
R
8
is hydroxyl, mercapto, C
1-18
acyloxy or C
1-19
hydrocarbon group-substituting oxycarbonyloxy; and
R
9
is a C
1-14
hydrocarbon group in which —CH
2
— not directly bound to the purine skeleton and CH
2
in —CH
3
not directly bound to the purine skeleton may be substituted by carbonyl, sulfonyl, —O— or —S—; ═CH
2
may be substituted by ═O or ═S; C—H in —CH
2
— not directly bound to the purine skeleton, C—H in —CH
3
not directly bound to the purine skeleton, C—H in >CH— not directly bound to the purine skeleton, C—H in ═CH— not directly bound to the purine skeleton, C—H in ═CH
2
and C—H in ≡CH may be substituted by N, C-halogen or C—CN;
or its tautomer or a pharmaceutically acceptable salt of the purine derivative or the tautomer.
Specifically, the Th2-selective immune response inhibitor and the immune response regulator of the invention are used as an anti-allergic agent; they are pharmaceuticals to be administered for alleviating the conditions of allergic diseases developed by various causes or for preventing the manifestation of symptoms. Specifically, the above-mentioned allergic diseases include allergic dermatitis, allergic rhinitis, atopic dermatitis, asthma (atopic asthma, non-atopic asthma) and the like. The Th2-selective immune response inhibitor and the immune response regulator of the invention are used as a therapeutic or prophylactic for such diseases. Furthermore, they are used as a therapeutic or prophylactic for autoimmune diseases such as systemic lupus erythematosus having similar uncomfortable symptoms.
Hereinbelow, the purine derivative represented by General Formula (I) which is used as an active ingredient in the present invention will be described in more detail.
First, the hydrocarbon group in General Formula (I) described above includes any of straight- or branched-chain hydrocarbon groups; monocyclic hydrocarbon groups without or with a side chain(s); polycyclic hydrocarbon groups without or with a side chain(s); spiro hydrocarbon groups without or with a side chain(s); ring-assembling structural hydrocarbon groups without or with a side chain(s); or chain hydrocarbon groups substituted by the above-described cyclic hydrocarbon group(s). The hydrocarbon group in General Formula (I) also includes both saturated hydrocarbon groups and unsaturated hydrocarbon groups, but it does not i
Isobe Yoshiaki
Matsui Hiroyuki
Ogita Haruhisa
Takaku Haruo
Tobe Masanori
Fish & Richardson P.C.
Japan Energy Corporation
Jarvis William R. A.
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